Over the last decade, major advances have been made in the understanding of the biology of the mammalian tachykinin neuropeptides. It is now well established that substance-P (1), neurokinin A (NKA) (2), and neurokinin B (NKB) (3), all of which share a common C-terminal sequence Phe-X-Gly-Leu-Met-NH2, (Nakanishi S., Physiol. Rev., 1987;67:117), are widely distributed throughout the periphery and central nervous system (CNS) where they appear to interact with at least three receptor types referred to as NK1, NK2, and NK3, (Guard S., et al., Neurosci. Int., 1991;18:149). Substance-P displays highest affinity for NK1 receptors, whereas NKA and NKB bind preferentially to NK2 and NK3 receptors, respectively. Recently, all three receptors have been cloned and sequenced and shown to be members of the G-protein-linked xe2x80x9csuper familyxe2x80x9d of receptors (Nakanishi S., Annu. Rev. Neurosci., 1991;14:123). A wealth of evidence supports the involvement of tachykinin neuropeptides in a variety of biological activities including pain transmission, vasodilation, smooth muscle contraction, bronchoconstriction, activation of the immune system (inflammatory pain), and neurogenic inflammation (Pernow B., Pharmacol. Rev., 1983;35:85). However, to date, a detailed understanding of the physiological roles of tachykinin neuropeptides has been severely hampered by a lack of selective, high affinity, metabolically stable tachykinin receptor antagonists that possess both good bioavailability and CNS penetration. Although several tachykinin receptor antagonists have been described (Tomczuk B. E., et al., Current Opinions in Therapeutic Patents, 1991; 1:197), most have been developed through the modification and/or deletion of one or more of the amino acids that comprise the endogenous mammalian tachykinins such that the resulting molecules are still peptides that possess poor pharmacokinetic properties and limited in vivo activities.
However, since 1991, a number of high-affinity nonpeptide antagonists have been reported. Snider R. M., et al., (Science, 1991;251:435), and Garret C., et al., (Proc. Natl. Acad. Sci., 1991;88:10208), described CP-96,345 and RP 67580, respectively, as antagonists at the NK1 receptor, while Advenier C., et al., (Brit. J. Pharmacol., 1992;105:78), presented data on SR 48968 showing its high affinity and selectivity for NK2 receptors. More recently Macleod, et al., (J. Med. Chem., 1993;36:2044) have published on a novel series of tryptophan derivatives as NK1 receptor antagonists. It is of interest that most of the nonpeptide tachykinin receptor antagonists described to date arose, either directly or indirectly, out of the screening of large compound collections using a robust radioligand binding assay as the primary screen. Recently, FK 888, a xe2x80x9cdipeptidexe2x80x9d with high affinity for the NK1 receptor was described (Fujii J., et al., Neuropeptide, 1992;22:24). Only one NK3 receptor selective ligand, SR 142801, has been published on to date (Edmonds-Alt, et al., Life Sciences, 1995;56:27).
International Publication Numbers WO 93/01169, WO 93/01165, and WO 93/001160 cover certain nonpeptide tachykinin receptor antagonists.
NKB and also NK3 receptors are distributed throughout the periphery and central nervous system (Maggi, et al., J. Auton. Pharmacol., 1993;13:23). NKB is believed to mediate a variety of biological actions via the NK3 receptor including gastric acid secretion; appetite regulation; modulation of serotonergic, cholinergic, and dopaminergic systems; smooth muscle contraction and neuronal excitation. Recent publications descriptive of this art include Polidor, et al., Neuroscience Letts., 1989;103:320; Massi, et al., Neuroscience Letts., 1988;92:341, and Improta, et al., Peptides, 1991;12:1433. Due to its actions with dopaminergic (Elliott, et al., Neuropeptides, 1991;19:119), cholinergic (Stoessl, et al., Psycho. Pharmacol., 1988;95:502), and serotonergic (Stoessl, et al., Neuroscience Letts., 1987;80:321) systems, NKB may play a role in psychotic behavior, memory functions, and depression.
Accordingly, compounds capable of antagonizing the effects of NKB at NK3 receptors will be useful in treating or preventing a variety of disorders including pain, depression, anxiety, panic, schizophrenia, neuralgia, addiction disorders, inflammatory diseases; gastrointestinal disorders including colitis, Crohn""s disease, inflammatory bowel disorder, and satiety; vascular disorders such as angina and migraine and neuropathological disorders such as Parkinsonism and Alzheimer""s.
The instant invention is a compound of formula 
or a pharmaceutically acceptable salt thereof wherein:
R1 is straight or branched alkyl of from 5 to 15 carbon atoms, aryl, or heteroaryl;
R2 is hydrogen, hydroxy, amino, or thiol;
R3 is aryl, arylsulfonylmethyl, or saturated or unsaturated heterocycle;
R4 is from 1 to 4 groups each independently selected from halogen, alkyl, hydroxy, and alkoxy;
n is an integer of from 2 to 6; and the (CH2) group can be replaced by oxygen, nitrogen, or sulphur.
Preferred compounds of the invention are those of Formula I wherein:
R1 is phenyl, naphthyl, piperidinyl, imidazolyl, or tetrazole;
R2 is hydrogen, hydroxy, or amino;
R3 is phenyl, fluorophenyl, hydroxyphenyl, or phenylsulfonylmethyl;
R4 is dichloro, difluoro, dimethoxy, or dimethyl; and
n is an integer of from 2 to 6.
More preferred compounds of the invention are those of Formula I wherein:
R1 is phenyl, naphthyl, piperidinyl, or imidazolyl;
R2 is hydrogen or hydroxy;
R3 is phenyl, 4-fluorophenyl, 4-hydroxyphenyl, or phenylsulfonylmethyl;
R4 is 3,4-dichlorophenyl; and
n is the integer 2 to 4.
Still more preferred compounds of the instant invention are those of Formula I wherein:
R1 is phenyl;
R2 is hydrogen or hydroxy;
R3 is phenylsulfonylmethyl or phenyl;
R4 is 3,4-dichloro; and
n is 3.
The most preferred compounds of the invention are selected from but not limited to:
(R)-{3-(3,4-Dichloro-phenyl)-3-[3-(4-phenyl-piperidin-1-yl)-propyl]-piperidin-1-yl}-phenyl-methanone monohydrochloride;
(S)-{3-(3,4-Dichloro-phenyl)-3-[3-(4-hydroxy-4-phenyl-piperidin-1-yl)-propyl]-piperidin-1-yl}-phenyl-methanone monohydrochloride;
(S)-[3-[3-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-yl)-propyl]-3-(3,4-dichloro-phenyl)-piperidin-1-yl]-phenyl-methanone monohydrochloride;
(R)-{3-(3,4-Dichloro-phenyl)-3-[3-(4-hydroxy-4-phenyl-piperidin-1-yl)-propyl]-piperidin-1-yl}-naphthalene-2-yl-methanone;
(R)-{3-(3,4-Dichloro-phenyl)-3-[3-(4-hydroxy-4-phenyl-piperidin-1-yl)-propyl]-piperidin-1-yl}-pyridin-4-yl-methanone;
N-(1-{3-[3-(3,4-Dichloro-phenyl)-1-(1H-imidazole-2-carbonyl)-piperidin-3-yl]-propyl}-4-phenyl-piperidin-4-yl)-acetamide;
(R)-{3-(3,4-Dichloro-phenyl)-3-[3-(4-hydroxy-4-phenyl-piperidin-1-yl)-propyl]-piperidin-1-yl}-phenyl-methanone;
(R)-{3-(3,4-Dichloro-phenyl)-3-[3-(4-phenyl-piperidin-1-yl)-propyl]-piperidin-1-yl}-phenyl-methanone;
(3-(3,4-Dichloro-phenyl)-3-{3-[4-(4-fluoro-phenyl)-4-hydroxy-piperidin-1-yl]-propyl}-piperidin-1-yl)-phenyl-methanone;
[3-[3-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-yl)propyl]-3-(3,4-dichloro-phenyl)-piperidin-1-yl]-phenyl-methanone;
{3-(4-Fluoro-phenyl)-3-[3-(4-hydroxy-4-phenyl-piperidin-1-yl)-propyl]-piperidin-1-yl}-phenyl-methanone;
{3-(3,4-Dimethoxy-phenyl)-3-[3-(4-hydroxy-4-phenyl-piperidin-1-yl)-propyl]-piperidin-1-yl}-phenyl-methanone;
{3-(3,4-Dimethyl-phenyl)-3-[3-(4-hydroxy-4-phenyl-piperidin-1-yl)-propyl]-piperidin-1-yl}-phenyl-methanone;
[3-[3-(4-Hydroxy-4-phenyl-piperidin-1-yl)-propyl]-3-(3,4,5-trichloro-phenyl)-piperidin-1-yl]-phenyl-methanone;
{3-(3,4-Dichloro-phenyl)-3-[4-(4-hydroxy-4-phenyl-piperidin-1-yl)-butyl]-piperidin-1-yl}-phenyl-methanone;
{3-(3,4-Dichloro-phenyl)-3-[6-(4-hydroxy-4-phenyl-piperidin-1-yl)-hexyl]-piperidin-1-yl}-phenyl-methanone;
[3-{2-[(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-ylmethyl)-amino]-ethyl}-3-(3,4-dichloro-phenyl)-piperidin-1-yl]-phenyl-methanone;
[3-{2-[(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-ylmethyl)-methyl-amino]-ethyl}-3-(3,4-dichlorophenyl)-piperidin-1-yl]-phenyl-methanone;
[3-[2-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-ylmethoxy)-ethyl]-3-(3,4-dichlorophenyl)-piperidin-1-yl]-phenyl-methanone;
[3-[2-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-ylmethylsulfanyl)-ethyl]-3-(3,4-dichloro-phenyl)-piperidin-1-yl]-phenyl-methanone;
(3-(3,4-Dichloro-phenyl)-3-{2-[(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-amino]-ethyl}-piperidin-1-yl)-phenyl-methanone;
(3-(3,4-Dichloro-phenyl)-3-{2-[(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-methyl-amino]-ethyl}-piperidin-1-yl)-phenyl-methanone;
{3-(3,4-Dichloro-phenyl)-3-[2-(4-hydroxy-4-phenyl-piperidin-1-ylmethoxy)-ethyl]-piperidin-1-yl}-phenyl-methanone;
{3-(3,4-Dichloro-phenyl)-3-[2-(4-hydroxy-4-phenyl-piperidin-1-ylmethylsulfanyl)-ethyl]-piperidin-1-yl}-phenyl-methanone;
[3-{[2-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-yl)-ethylamino]-methyl}-3-(3,4-dichloro-phenyl)-piperidin-1-yl]-phenyl-methanone;
[3-({[2-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-yl)-ethyl]-methyl-amino}-methyl)-3-(3,4-dichloro-phenyl)-piperidin-1-yl]-phenyl-methanone;
[3-[2-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-yl)-ethoxymethyl]-3-(3,4-dichlorophenyl)-piperidin-1-yl]-phenyl-methanone;
[3-[2-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-yl)-ethylsulfanylmethyl]-3-(3,4-dichloro-phenyl)-piperidin-1-yl]-phenyl-methanone;
(3-(3,4-Dichloro-phenyl)-3-{[2-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethylamino]-methyl}-piperidin-1-yl)-phenyl-methanone;
[3-(3,4-Dichloro-phenyl)-3-({[2-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethyl]-methyl-amino}-methyl)-piperidin-1-yl]-phenyl-methanone;
{3-(3,4-Dichloro-phenyl)-3-[2-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethoxymethyl]-piperidin-1-yl}-phenyl-methanone;
{3-(3,4-Dichloro-phenyl)-3-[2-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethylsulfanylmethyl]-piperidin-1-yl}-phenyl-methanone;
[3-[(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-ylmethyl)-amino]-3-(3,4-Dichloro-phenyl)piperidin-1-yl]-phenyl-methanone;
[3-[2-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-yl)-ethylamino]-3-(3,4-dichlorophenyl)-piperidin-1-yl]-phenyl-methanone;
[3-[3-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-yl)-propylamino]-3-(3,4-dichlorophenyl)-piperidin-1-yl]-phenyl-methanone;
[3-[(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-ylmethyl)-methyl-amino]-3-(3,4-dichlorophenyl)-piperidin-1-yl]-phenyl-methanone;
[3-{[2-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-yl)-ethyl]-methyl-amino}-3-(3,4-dichloro-phenyl)-piperidin-1-yl]-phenyl-methanone;
[3-{[3-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-yl)-propyl]-methyl-amino}-3-(3,4-dichloro-phenyl)-piperidin-1-yl]-phenyl-methanone;
[3-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-ylmethoxy)-3-(3,4-dichloro-phenyl)-piperidin-1-yl]-phenyl-methanone;
[3-[2-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-yl)-ethoxy]-3-(3,4-dichlorophenyl)-piperidin-1-yl]-phenyl-methanone;
[3-[3-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-yl)-propoxy]-3-(3,4-dichlorophenyl)-piperidin-1-yl]-phenyl-methanone;
[3-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-ylmethylsulfanyl)-3-(3,4-dichlorophenyl)-piperidin-1-yl]-phenyl-methanone;
[3-[2-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-yl)-ethylsulfanyl]-3-(3,4-dichlorophenyl)-piperidin-1-yl]-phenyl-methanone;
[3-[3-(4-Benzenesulfonylmethyl-4-hydroxy-piperidin-1-yl)-propylsulfanyl]-3-(3,4-dichlorophenyl)-piperidin-1-yl]-phenyl-methanone;
{3-(3,4-Dichloro-phenyl)-3-[(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-amino]-piperidin-1-yl}-phenyl-methanone;
{3-(3,4-Dichloro-phenyl)-3-[2-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethylamino]-piperidin-1-yl}-phenyl-methanone;
{3-(3,4-Dichloro-phenyl)-3-[3-(4-hydroxy-4-phenyl-piperidin-1-yl)-propylamino]-piperidin-1-yl}-phenyl-methanone;
{3-(3,4-Dichloro-phenyl)-3-[(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-methyl-amino]-piperidin-1-yl}-phenyl-methanone;
(3-(3,4-Dichloro-phenyl)-3-{[2-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethyl]-methyl-amino}-piperidin-1-yl)-phenyl-methanone;
(3-(3,4-Dichloro-phenyl)-3-{[3-(4-hydroxy-4-phenyl-piperidin-1-yl)-propyl]-methyl-amino}-piperidin-1-yl)-phenyl-methanone;
[3-(3,4-Dichloro-phenyl)-3-(4-hydroxy-4-phenyl-piperidin-1-ylmethoxy)-piperidin-1-yl]-phenyl-methanone;
{3-(3,4-Dichloro-phenyl)-3-[2-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethoxy]-piperidin-1-yl}-phenyl-methanone;
{3-(3,4-Dichloro-phenyl)-3-[3-(4-hydroxy-4-phenyl-piperidin-1-yl)-propoxy]-piperidin-1-yl}-phenyl-methanone;
[3-(3,4-Dichloro-phenyl)-3-(4-hydroxy-4-phenyl-piperidin-1-ylmethylsulfanyl)-piperidin-1-yl]-phenyl-methanone;
{3-(3,4-Dichloro-phenyl)-3-[2-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethylsulfanyl]-piperidin-1-yl}-phenyl-methanone; and
{3-(3,4-Dichloro-phenyl)-3-[3-(4-hydroxy-4-phenyl-piperidin-1-yl)-propylsulfanyl]-piperidin-1-yl}-phenyl-methanone.
Another aspect of the invention is a pharmaceutical composition containing one or more compound of Formula I above in a therapeutically effective amount together with a pharmaceutically acceptable carrier.
The compounds of the invention are useful in the treatment of central nervous system disorders such as anxiety, emesis, depression, psychoses, and schizophrenia. They are also useful in the treatment of inflammatory disease, pain, migraine, asthma, and emesis. They are also useful in the treatment of Alzheimer""s disease and Parkinsonism.